ClinVar Miner

Submissions for variant NM_004771.4(MMP20):c.103A>C (p.Arg35=)

gnomAD frequency: 0.00009  dbSNP: rs61751462
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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Illumina Laboratory Services, Illumina RCV001105365 SCV001262324 uncertain significance Amelogenesis imperfecta hypomaturation type 2A2 2018-01-13 criteria provided, single submitter clinical testing This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease.
Ambry Genetics RCV003346319 SCV004074438 likely benign Inborn genetic diseases 2023-07-26 criteria provided, single submitter clinical testing This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute RCV001105365 SCV005085977 pathogenic Amelogenesis imperfecta hypomaturation type 2A2 2023-12-21 criteria provided, single submitter clinical testing Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with amelogenesis imperfecta, type IIA2 (MIM#612529). (I) 0106 - This gene is associated with autosomal recessive disease. (I) 0209 - Splice site variant that may affect splicing of the transcript with an uncertain effect on protein sequence. One publication demonstrated that in a mini-gene assay of exon 1 this synonymous variant resulted in altered splicing when compared to the wild-type, however the biological relevance of this outcome was not further assessed (PMID: 31999931). (SP) 0251 - This variant is heterozygous. (I) 0304 - Variant is present in gnomAD (v2) <0.01 for a recessive condition (41 heterozygotes, 0 homozygotes). (SP) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. ClinVar contains an older VUS entry. This variant has also been observed in homozygous and compound heterozygous individuals with amelogenesis imperfecta, including individuals compound heterozygous with NM_004771.3(MMP20):c.954-2A>T (PMID: 37228816, 31999931, 26502894). (SP) 0905 - No published segregation evidence has been identified for this variant. (I) 1201 - Heterozygous variant detected in trans with a second pathogenic heterozygous variant (NM_004771.3(MMP20):c.954-2A>T) in a recessive disease. (SP) 1206 - This variant has been shown to be paternally inherited (by trio analysis). (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign

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